Clostridium difficile, also known as C. difficile or C. diff., is an anaerobic, gram positive, spore-forming bacillus. Under certain circumstances, C. diff. colonizes the large bowel of patients and produces two cytotoxins, toxins A and B, that are responsible for causing diarrhea and colitis. The association between the release of these cytotoxins and antibiotic-associated diarrhea was first reported in 1978.
Clostridium difficile-associated disease, or CDAD, is caused by C. difficile. CDAD is sometimes referred to as C. difficile colitis or pseudomembranous colitis. CDAD is a disease that primarily threatens older patients in hospitals and elder care facilities. This virulent bacterial infection that causes severe diarrhea is quick to spread and difficult to remove from hospital and long term care environments. While those infected are often only mildly sick, CDAD can advance to a point where it irreversibly damages the colon. In severe cases, CDAD can cause sepsis, multiorgan failure, intestinal perforation and even death. In fact, according to the Centers for Disease Control and Prevention (CDC), CDAD has caused more deaths in the United States than all other intestinal infections combined.
The incidence of CDAD has exploded in the last decade. As Clostridia are spore-forming bacteria, diarrheal patients in hospitals or other settings shed thousands of spores. These spores are resistant to most germicidal agents and can persist in hospital and nursing home wards for long periods of time. There is also concern that C. diff infection is becoming more prevalent outside of hospital settings (community-acquired), due to the emergence of hypervirulent and antibiotic resistant strains and that infection can and will occur in the absence of prior antibiotic exposure.
CDAD treatment often involves cessation of the inciting antibiotic, C. difficile-targeted antibiotic therapy, electrolyte normalization, fluid replacement, probiotics, and bile-acid sequestrants (e.g., cholestyramine). If CDAD continues despite stopping antibiotics, or if the diarrhea is severe, patients with CDAD are treated with antibiotics including metronidazole or oral vancomycin. Metronidazole is used as a first course of therapy and for more moderate cases of CDAD. Vancomycin, a more powerful therapy, is usually prescribed for more severe cases.
Knowledge of the epidemiology, pathogenesis and treatment of CDAD has increased substantially during the past three decades. However, this increased knowledge has not led to a decline in disease frequency or severity. To the contrary, since 2000, the incidence of CDAD and mortality rates from the disease have increased dramatically. These increases are fueled in part by microbial virulence and antibiotic resistance. However, host factors such as increasing age, disease co-morbidities and immune senescence as well as environmental factors such as antibiotic use and contamination of healthcare facilities by C. difficile spores are also instrumental. These developments (increasing CDAD incidence, severity and death rates) clearly demonstrate that current approaches to disease prevention and treatment are inadequate and that new approaches are needed.
It is therefore a primary objective of the present invention to provide an improved method and means of treating CDAD.
It is a further objective of the present invention to provide a method of preventing reoccurrence of C. diff infection following its initial successful treatment.
These and other objects of the invention will become apparent from the detailed description of the invention which follows.